1. Field of the Invention
The present invention is directed to novel transient pro-drug forms of certain xanthine derivatives useful in (1) elevating intracellular cyclic AMP* levels, and (2) the treatment of psoriasis in warm-blooded animals. FNT *Adenosine monophosphate
For the purposes of this application, the term "pro-drug" denotes a derivative of a known and proven prior art xanthine compound (e.g., theophylline), which derivative, when administered topically to a warm-blooded animal, "cleaves" in such a manner as to release the proven drug form in the dermal tissue thereof.
The term "transient" denotes dermal enzymatic and/or chemical hydrolytic "cleavage" of the compounds of the instant invention in such a manner that the proven drug form (parent xanthine compound, e.g., theophylline) is released and the remaining "cleaved" moiety remains nontoxic and metabolized in such a manner that nontoxic, metabolic products are produced.
2. Description of the Prior Art
The development of pro-drug forms of certain xanthine compounds such as theophylline was initiated in order that such compounds could be used in the treatment of psoriasis. The rational use of theophylline and other chemically related xanthine compounds to treat psoriasis is based on three documented observations:
a. that psoriatic conditions stem from increased cell division of the skin which in many ways mimics cancerous cell division, J. J. Voorhees, E. A. Duell, M. Stawiski and E. K, Harrell, Clin. Pharmacol. Therap., 16, 919 (1974);
b. that theophylline and similarly related xanthine compounds decrease the degradation of cyclic AMP by inhibiting phosphodiesterase activity, E. W. Sutherland and T. W. Rall, J. Biol. Chem., 232, 1077 (1958); and
c. that cyclic AMP can inhibit malignant cell growth in culture, G. S. Johnson, R. M. Friedman, I. Pastan, Proc. Natl. Acad. Sci. U.S.A., 68, 425 (1971) and A. N. Hsie and T. T. Puck, Ibid., p. 1316, respectively.
A direct correlation between percutaneous absorption and partition coefficients of the absorbed compound in water and some lipid-like materials, e.g., oil, heptane octanol has been shown. See, M. Katz and Z. I. Shaiki, J. Pharm. Sci., 54, 591 (1965) and J. E. Treherne, J. Physiol., 133, 171 (1956). The closer this partition coefficient is to unity, the better the compound is absorbed, providing, however, the compound in question has appreciable solubility in both the water and lipid phase. However, if anything, the skin is more permeable to lipid soluble substances. See, J. H. Wills, "Percutaneous Absorption" in Pharmacology and The Skin, W. Montagny, E. J. Van Scott and R. B. Stoughton, Ed., Chapter XII, Appleton-Century Grofts, New York, New York, 1972, p. 172. Certain Xanthine compounds, such as theophylline, on the other hand, are almost insoluble in lipid-like solvents (e.g., heptane). Consequently, their use in the treatment of psoriasis has heretofore been limited. Moreover, the above also makes it very clear that the target pro-drug of the xanthine compound employed should have an increased lipid solubility and a partition coefficient near unity if it is to be absorbed percutaneously and reach the site where therapeusis is required.
The remaining criteria for the target pro-drug is that it undergo rapid hydrolysis once it reaches its site of therapeutic activity. One candidate which appears to meet the above criteria is the 7-acyloxymethyl derivative of theophylline. Acyloxymethyl esters of ampicillin have been shown to be readily hydrolyzed by esterases and other enzymes present in serum and tissue homogenates of man. See, W. V. Daehne, et al., J. Med. Chem., 13, 607 (1970). In the case of theophylline, hydrolysis would initially lead to the 7-hydroxymethyl derivative which the present inventors have found to be extremely unstable in water. Accordingly, it would generate theophylline in vivo. It has also been found that incorporation of a long chain aliphatic acid into theophylline or the remaining parent xanthine compounds of the instant invention increases the lipid solubility of the same.